Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs

ABSTRACT

Different polymorphs of bromfenac sodium may be prepared and interconverted using crystallization/recrystallization, drying and/or hydration techniques.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/925,171, filed Jun. 24, 2013 which is a continuation of U.S. patentapplication Ser. No. 13/626,304, filed Sep. 25, 2012 (now U.S. Pat. No.8,481,780, issued on Jul. 9, 2013), which is a continuation of U.S.patent application Ser. No. 12/891,007, filed Sep. 27, 2010 (now U.S.Pat. No. 8,299,293, issued on Oct. 30, 2012), and claims priority toU.S. Provisional Patent Application No. 61/251,925, filed Oct. 15, 2009,the disclosures of all of which are incorporated herein by reference intheir entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to novel polymorphs of bromfenac sodium,to novel, reproducible processes for their preparation, and topharmaceutical compositions containing such polymorphs.

DISCUSSION OF THE RELATED ART

Bromfenac sodium (which is the sodium salt of 2-amino-3-(4-bromobenzoyl)phenyl acetic acid, also sometimes referred to as sodium2-amino-3-(4-bromobenzoyl)phenyl acetate sesquihydrate, having theempirical formula C₁₅H₁₁BrNNaO₃.1.5H₂O) is a non-steroidalanti-inflammatory drug (NSAID) with analgesic properties. It wasinitially marketed as an oral suspension under the trade name DURACT butwas withdrawn under the brand name XIBROM. The Food and DrugAdministration approved this product in 2005 for use in ophthalmicsurgery including postoperative inflammation, reduction of pain aftercataract and refractive surgery and management of macular edema aftercataract surgery. XIBROM ophthalmic solution contains 1.035 mg bromfenacsodium, equivalent to 0.9 mg bromfenac free acid per mL of solution,giving a 0.09% sterile topical ophthalmic formulation with a pH of 8.3.

A survey of the literature on bromfenac sodium did not provide anyreference to its crystal structure or the possibility of differentpolymorphs. Information about the solid-state properties of a drugsubstance is important. For example, different forms may havesignificantly different solubilities. Also the handling and stability ofa drug substance may depend critically on the solid form.

Polymorphism is defined as “the ability of a compound to crystallize inmore than one distinct crystal species” and different crystalarrangements of the same chemical composition are termed polymorphs.Polymorphs of the same compound arise due to differences in the internalarrangement of atoms and have different free energies and thereforedifferent physical properties such as solubility, chemical stability,melting point, density, flow properties, bioavailability and so forth.

BRIEF SUMMARY OF THE INVENTION

It has now been discovered that bromfenac sodium can be prepared inthree well-defined and consistently reproducible crystalline forms, aswell as mixtures of certain of these crystalline forms. Moreover,reliable and scalable methods for interconverting these crystallineforms have been developed. The bromfenac sodium polymorphs provided bythe present invention are useful active ingredients in pharmaceuticalformulations.

In one aspect of the invention, bromfenac sodium Form I is provided,preferably substantially free of any other physical forms of bromfenacsodium. This polymorph of bromfenac sodium is a highly crystallineconsistent polymorph and is a sesquihydrate that is stable. Bromfenacsodium Form I may be prepared by a process comprising crystallizing orrecrystallizing bromfenac sodium from a solvent mixture comprisingwater, at least one dialkoxyalkane, and at least one anti-solvent. Thepresent invention permits bromfenac sodium Form I to be obtained inhighly pure form; in particular, bromfenac sodium Form I that has verylow levels of residual sodium hydroxide and other reagents (carried overfrom the synthesis of the bromfenac sodium), organic solvents, processimpurities, and bromfenac sodium degradation products may be prepared.

In another aspect of the invention, bromfenac sodium Form II isprovided. Bromfenac sodium Form II is a hydrate of bromfenac sodiumcontaining less than 1.5 moles of water per mole of bromfenac sodium(e.g., about 1 mole water per mole of bromfenac sodium).

In still another aspect of the invention, bromfenac sodium Form III isprovided. Bromfenac sodium Form III is a non-hydrated polymorph ofbromfenac sodium that may be prepared by a process comprisingcrystallizing or recrystallizing bromfenac sodium from a solvent mixturecomprising water and at least one alcohol. Another method for preparingbromfenac sodium Form III comprises treating7-(4-bromobenzoyl)indol-2-one with sodium hydroxide in a mixture ofwater, at least one alcohol, and at least one aromatic hydrocarbon toobtain a bromfenac sodium reaction mixture and combining at least oneanti-solvent with the bromfenac sodium reaction mixture.

Mixtures comprised of bromfenac sodium Form I and bromfenac sodium FormII are also furnished by the present invention. Such mixtures may beprepared by crystallizing or recrystallizing bromfenac sodium from asolvent mixture comprising water, at least one dialkoxyalkane, and atleast one anti-solvent to give an initial solid product and drying theinitial solid product under vacuum.

Also provided by the present invention is a method for convertingbromfenac sodium Form I into bromfenac sodium Form II, comprising dryingbromfenac sodium Form I under vacuum.

The present invention also provides a method for converting a materialselected from bromfenac sodium Form I, bromfenac sodium Form II or amixture of bromfenac sodium Form I and bromfenac sodium Form II intobromfenac sodium Form III, comprising crystallizing or recrystallizingthe material from a solvent mixture comprised of water and at least onealcohol.

In another aspect of the invention, bromfenac sodium Form II isconverted into bromfenac sodium Form I by a process comprising hydratingthe bromfenac sodium Form II.

A method for converting bromfenac sodium Form III into bromfenac sodiumForm I is additionally provided by the present invention, wherein themethod comprises crystallizing or recrystallizing the bromfenac sodiumForm III from a solvent mixture comprised of water, at least onedialkoxyalkane, and at least one anti-solvent such as a dialkylether toyield an intermediate product containing less than 1.5 moles of waterper mole of bromfenac sodium and hydrating the intermediate product.

In still another aspect of the invention, bromfenac sodium Form I may beconverted into bromfenac sodium Form III by a process comprisingcrystallizing or recrystallizing bromfenac sodium Form I from a solventmixture comprising water and at least one alcohol.

A method for converting bromfenac sodium Form III into bromfenac sodiumForm II is further provided by the present invention, wherein the methodcomprises crystallizing or recrystallizing bromfenac sodium Form IIIfrom a solvent mixture comprised of water, at least one dialkoxyalkane,and at least one anti-solvent such as a dialkyl ether to obtain anintermediate product and drying the intermediate product under vacuum.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a representative x-ray powder diffraction (XRPD) pattern ofbromfenac sodium Form I in accordance with the invention.

FIG. 2 is an FT-IR spectrum of a representative sample of bromfenacsodium Form I in accordance with the invention.

FIG. 3 is a representative x-ray powder diffraction (XRPD) pattern ofbromfenac sodium Form III in accordance with the invention.

FIG. 4 is an FT-IR spectrum of a representative sample of bromfenacsodium Form III in accordance with the invention.

FIG. 5 is an x-ray powder diffraction (XRPD) pattern of a mixture ofbromfenac sodium Form I and bromfenac sodium Form II in accordance withthe invention.

FIG. 6 is a deduced XRPD pattern for bromfenac sodium Form II inaccordance with the invention.

FIG. 7 illustrates in schematic form certain of the polymorphinterconversions capable of being realized through the invention.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The bromfenac sodium to be used as a starting material for thepreparation of the bromfenac sodium polymorphs which are the subject ofthe present invention may be synthesized using any of the methods knownin the art. For example, bromfenac sodium can be produced as describedin Walsh et al., Journal of Medicinal Chemistry, Volume 27, pages1379-1388 (1984) or U.S. Pat. No. 4,683,242 (Example 74), each of whichis incorporated herein by reference in its entirety for all purposes.

Bromfenac sodium Form I is a highly crystalline polymorph of bromfenacprovided by the present invention which is a stable sesquihydrate. FIG.1 is a representative x-ray powder diffraction (XRPD) pattern ofbromfenac sodium Form I. Table A lists a d-spacing/% intensity patterntypical of bromfenac sodium Form I (peaks having a relative intensity of<2.0% are not listed). The powder x-ray diffraction pattern of bromfenacsodium Form I may have main peaks expressed as 2-theta at about 4.4,8.8, 9.4, 12.1, 15.2, 15.9, 17.6, 18.2, 18.8, 20.2, 21.2, 24.7, 28.4,and 32.4 degrees. FIG. 2 shows an FT-IR spectrum of a representativesample of bromfenac sodium Form I. In one embodiment, the bromfenacsodium Form I is purified and isolated such that it is substantiallyfree of any other physical forms of bromfenac sodium. “Substantiallyfree” in the context of the present invention means that the powderx-ray diffraction pattern does not exhibit any visible peaks associatedwith other bromfenac sodium polymorphs.

The present invention enables the preparation of bromfenac sodium Form Iwhich is not only substantially free from any other physical forms ofbromfenac sodium but also has a very high level of chemical purity. Thatis, bromfenac sodium Form I prepared in accordance with the inventionmay be substantially free of process impurities (i.e., impurities thatare structurally related to bromfenac sodium and that are carriedthrough or produced during the synthetic process, such as precursors ofthe bromfenac sodium), degradation products of bromfenac sodium, as wellas substances unrelated to bromfenac sodium such as residual solvents,metals or reagents carried through from the process of manufacture. Forexample, in one embodiment, the bromfenac sodium Form I product does notcontain more than 0.15% AUC (alternatively, not more than 0.10% AUC) ofany process impurity or bromfenac sodium degradation product, asmeasured by high pressure liquid chromatography. As another example, thepresent invention enables the preparation of bromfenac sodium Form Ithat is substantially free of residual sodium hydroxide, as evidenced bya relatively low pH when the bromfenac sodium Form I is dissolved inwater. High levels of residual sodium hydroxide have been found toincrease the hygroscopicity of the bromfenac sodium Form I product(i.e., it exhibits a greater tendency to absorb more than 1.5 moles ofwater per mole of bromfenac sodium). Preferably, the pH of such asolution is not more than 11, or, more preferably, not more than 10.6.In another aspect, the bromfenac sodium Form I may contain less than 200ppm or less than 150 ppm organic solvent in total, as measured by gaschromatography. In still another aspect, the bromfenac sodium Form I maycontain less than 100 ppm aluminum, boron, and manganese in total and/orless than 30 ppm of each of these elements, as measured by InductivelyCoupled Plasma Optical Emission Spectroscopy (ICP-OES).

TABLE A Angle d value, 2-theta Angstrom Intensity % 15.2 5.80 100.0 18.84.69 12.5 17.6 5.00 10.9 24.7 3.59 10.3 21.2 4.17 9.3 20.2 4.37 9.1 32.42.75 9.1 8.8 10.0 8.9 9.4 9.38 7.6 28.4 3.12 7.4 18.2 4.85 7.3 12.1 7.275.8 15.9 5.55 5.7 4.4 20.01 5.1 22.1 4.00 4.5 13.2 6.68 3.8 21.9 4.043.8 30.6 2.91 3.2 40.9 2.20 3.0 25.9 3.42 2.3 29.6 3.01 2.3 31.2 2.852.3 26.5 3.35 2.2 10.0 8.76 2.2 23.4 3.79 2.0

Bromfenac sodium Form I may be prepared by a process comprisingcrystallizing and/or recrystallizing bromfenac sodium from a solventmixture comprising water, at least one dialkoxyalkane, and at least oneanti-solvent. The bromfenac sodium may be an initial or crude reactionproduct obtained by synthesizing bromfenac sodium from a suitableprecursor such as hydrolysis of the corresponding indolone. Thebromfenac sodium starting material may also be, for example, bromfenacsodium Form III. In addition to producing bromfenac sodium Form Icrystals which are substantially free of any other bromfenac sodiumpolymorphs, such crystallization and recrystallization processes providethe further advantage of facilitating the removal or reduction of otherimpurities in the bromfenac sodium starting material (e.g., unreacted orresidual reagents, byproducts, etc.). For example, the bromfenac sodiumstarting material may be a sample of bromfenac sodium Form I that iscontaminated with chemical impurities and/or minor amounts of one ormore other bromfenac polymorphs, wherein the recrystallization iseffective to improve the chemical and/or polymorphic purity of thesample.

In one aspect of the invention, the crystallization or recrystallizationis carried out by dissolving the starting bromfenac sodium in a mixtureof water and dialkoxyalkane to prepare an initial solution. The solventmixture may be heated to facilitate dissolution of the bromfenac sodium,e.g., to a temperature of from about 40 to about 90° C. One or moreanti-solvents are then added to the initial solution and the resultingmixture cooled (with or without agitation, such as by stirring), therebyallowing crystals of the desired bromfenac sodium Form I to precipitatefrom solution. For example, the mixture may be cooled to a temperatureof from about −10 to about 20° C. Seed crystals of bromfenac sodium FormI may be added to promote or accelerate the crystallization process. Ifthe initial sample of bromfenac sodium is contaminated with difficultlysoluble impurities, it may be desirable to filter the initial solutionand/or the mixture following addition of the anti-solvent (beforecooling) to remove such impurities. The bromfenac sodium Form I crystalsmay be collected and separated from the mother liquor by anyconventional separation technique such as filtration, decantation orcentrifugation, then subjected to further purification or processingsteps such as washing and/or drying if so desired. The separated motherliquor may be further treated to recover additional bromfenac sodiumForm I crystals and/or purified solvent for reuse in a crystallizationor recrystallization step. These techniques may be readily adapted foruse in connection with the practice of the othercrystallization/recrystallization processes described herein for otherbromfenac sodium polymorphs.

Suitable dialkoxyalkanes include, but are not limited to, hydrocarbonssubstituted with two or more C₁-C₄ alkoxy groups such as1,2-dimethoxyethane, 1,2-dimethoxypropane, 2,2-dimethoxypropane,diethoxymethane, 1,1-diethoxyethane, 1,2-diethoxyethane, and the likeand mixtures thereof. As used herein, the term anti-solvent refers to asolvent in which the desired product (i.e., the product beingcrystallized or recrystallized) is insoluble or essentially insoluble;the function of an anti-solvent thus is to reduce the solubility of theproduct in the solvent mixture and enhance the yield of precipitatedcrystals thereby recovered. Suitable anti-solvents includedialkylethers, particularly C₄-C₁₀ dialkyl ethers such as diethyl ether,dipropyl ether, diisopropyl ether, tert-butyl methyl ether, sec-butylmethyl ether, and the like and mixtures thereof. In one particularlyadvantageous embodiment, the solvent mixture is comprised of water,1,2-dimethoxyethane, and tert-butyl methyl ether.

If the bromfenac sodium starting material is contaminated withundesirably high levels of residual sodium (e.g., sodium hydroxide)carried over from a indolone hydrolysis procedure used to prepare thebromfenac sodium starting material, the following procedure may befollowed in order to obtain bromfenac sodium Form I that is free orsubstantially free of residual sodium contaminants. The bromfenac sodiumstarting material is dissolved in an aqueous dialkoxyalkane mixture(e.g., 10-20% v/v water in 1,2-dimethoxyethane (3-8 mL/g bromfenacsodium)) at a temperature (e.g., 55-80° C.) effective to form a solution(the mixture may be de-aerated by bubbling an inert gas such as nitrogenthrough the mixture prior to heating). The solution is then permitted tosettle until an aqueous layer forms (the aqueous layer will contain atleast a portion of the residual sodium contaminants). The organic layeris separated from the aqueous layer. While the organic layer is stillwarm (to avoid premature crystallization of the bromfenac sodium), afiltration may be performed to remove insoluble impurities. The organiclayer is then concentrated (under vacuum, for example) to form a wetslurry. The wet slurry is then combined with an anti-solvent such astert-butyl methyl ether. Crystalline, purified bromfenac sodium Form Iis thereafter recovered by filtration and may be washed (with additionalquantities of anti-solvent, for example) and dried (taking care to avoidover-drying, such that fewer than 1.5 moles water per mole bromfenacsodium are present in the final product).

In another aspect of the invention, the bromfenac sodium startingmaterial is dissolved in a mixture of 8-12% v/v water in1,2-dimethoxyethane (10-14 mL/g bromfenac sodium starting material) at50-75° C. to form a solution. The solution may be filtered while stillwarm to remove any insoluble impurities, then combined with a mixture of15-25% v/v 1,2-dimethoxyethane in tert-butyl methyl ether (8-12 mL/gbromfenac sodium starting material). Cooling the resulting mixture to atemperature of 0-15° C. over several (e.g., 4-8) hours providesbromfenac sodium Form I as a highly crystalline product, which may beseparated from the mother liquor and dried. If needed (for example,where the drying conditions used to remove the organic solvent from thecrystalline product result in fewer than 1.5 molecules of water permolecule of bromofenac sodium), hydration of the product therebyobtained may be carried out to ensure that the stable sesquihydrate isthe exclusive polymorph present.

Hydration may be effected by exposing the product to water, particularlywater vapor. For example, the product may be placed within an enclosedchamber under vacuum and water vapor (in the form of moist air or moistnitrogen, for instance) may be bled into the enclosed chamber.Alternatively, the product may be exposed to a moist atmosphere atapproximately atmospheric pressure within an enclosed chamber containinga source of liquid water.

If so desired, the above-described procedures for producing bromfenacsodium Form I may be adapted and modified so as to provide a productthat is a mixture of bromfenac sodium Form I and bromfenac sodium FormII. Bromfenac sodium Form II is a polymorph that is believed to be amonohydrate of bromfenac sodium, i.e., containing one water molecule permolecule of bromfenac sodium, and characterized by a powder x-raydiffraction pattern having main peaks expressed as 2-theta at about11.3, 14.4, 16.5, 17.3, 18.5, 19.4, 20.7, 21.0, 22.7, 29.0, 31.8, 34.1and 36.1 degrees. Drying the crystalline product initially obtained inthe crystallization process described above under a vacuum results inthe removal of some water of hydration from the sesquihydrate and theformation of the Form II polymorph, as evidenced by XRPD. The vacuumdrying conditions may be adjusted so as to vary the Form II polymorphcontent of the product obtained. For example, higher dryingtemperatures, lower pressures, and increased drying times will generallyall increase the amount of bromfenac sodium Form II present. It isbelieved that such parameters may be selected so as to provide bromfenacsodium Form II in substantially pure form (i.e., substantially free ofany bromfenac sodium Form I or any other polymorph).

However, since bromfenac sodium Form II is not stable, it should beprotected from atmospheric moisture or other sources of water to protectit from hydration and thus conversion to another polymorph such asbromfenac sodium Form I.

In another aspect of the invention, bromfenac sodium Form I may beprepared from bromfenac sodium Form III by a process comprising heating(preferably, after de-aeration) a mixture of bromfenac sodium Form III,water and a dialkoxyalkane (e.g., 1,2-dimethoxyethane) for a time and ata temperature effective to form an organic layer and an aqueous layer.Following separation of the aqueous layer and, optionally, filtration,the organic layer may be concentrated and combined with one or moreanti-solvents (e.g., a dialkylether) effective to causeprecipitation/crystallization of the desired bromfenac sodium Form I.The bromfenac sodium Form I thus obtained in solid form may be separatedfrom the mother liquor by filtration, decantation, centrifugation orlike method, washed (with anti-solvent, for example) if so desired, anddried (as noted above, overly harsh drying conditions should be avoided,if substantially pure bromfenac sodium Form I is desired).

Bromfenac sodium Form III is a crystalline polymorph of bromfenacprovided by the present invention which does not contain any water ofhydration. The rate of dissolution in water is significantly lower thanthe dissolution rate observed for bromfenac sodium Form I or otherhydrated forms of bromfenac sodium. Bromfenac sodium Form III has beenfound to be stable and exhibits little or no tendency to adsorb water(the water content of a sample subjected to wet nitrogen “hydration”conditions in a 30-35° C. vacuum oven (5 mm Hg) for 17 hours did notchange). FIG. 3 is a representative x-ray powder diffraction (XRPD)pattern of bromfenac sodium Form III. Table B lists a d-spacing/%intensity pattern typical of bromfenac sodium Form III. The powder x-raydiffraction pattern of bromfenac sodium Form III may have main peaksexpressed as 2-theta at about 12.2, 12.4, 14.1, 17.8, 19.6, 21.6, 22.4,24.0, 26.3 and 28.1 degrees. FIG. 4 shows the FT-IR spectrum of arepresentative sample of bromfenac sodium Form III. In one embodiment,the bromfenac sodium Form III is purified and isolated such that it issubstantially free of any other physical forms of bromfenac sodium.

TABLE B Angle d value, 2-theta Angstrom Intensity % 21.6 4.11 100.0 22.43.96 85.1 12.2 7.26 66.5 24.0 3.70 66.0 26.3 3.39 65.0 14.1 6.28 49.312.4 7.15 46.8 28.1 3.17 38.3 17.8 4.99 32.8 19.6 4.52 31.6 26.8 3.3228.8 36.2 2.48 27.8 16.3 5.44 25.3 26.7 3.34 24.8 31.7 2.82 23.3 31.02.88 23.3 29.7 3.00 20.2 18.3 4.84 18.9 27.2 3.27 18.3 35.7 2.51 16.239.4 2.29 15.7 43.4 2.08 15.6 30.7 2.91 15.5 47.8 1.90 15.2 34.9 2.5715.2 49.0 1.86 15.0 38.7 2.32 14.3 28.5 3.12 14.0 15.5 5.71 13.8 46.91.94 13.3 38.3 2.35 12.8

Bromfenac sodium Form III may be prepared by a process comprisingcrystallizing and/or recrystallizing bromfenac sodium from a solventmixture comprising water and at least one alcohol. This result wassurprising, in view of the fact that water is present in the solventmixture and thus would be expected to be incorporated into the bromfenacsodium crystals being formed during crystallization/recrystallization.The at least one alcohol may include one or more C₁-C₄ alcohols, inparticular at least one of ethanol or 2-propanol. Solvent mixturescomprised of water and 2-propanol (containing, for example, about 2 toabout 8° A) v/v water) have been found to be particularly suitable foruse as crystallization or recrystallization solvents to obtain bromfenacsodium Form III polymorph in substantially pure form. The bromfenacsodium starting material may, for example, be bromfenac sodium Form I,bromfenac sodium Form II, and/or a mixture of the Form I and Form IIpolymorphs.

Another method of preparing bromfenac sodium Form III involves treating7-(4-bromobenzoyl)indol-2-one with a sodium-containing base such assodium hydroxide in a medium comprised of water, at least one alcohol,and at least one aromatic hydrocarbon to obtain a reaction mixture thatis then combined with at least one anti-solvent. It may be desirable toheat the reaction mixture prior to being combined with the anti-solventat a temperature (e.g., about 50 to about 90° C.) and for a time (e.g.,about 3 to about 25 hours) effective to convert the indol-2-one to thecorresponding sodium salt. Following such heating, the reaction mixturemay be cooled somewhat (e.g., to about 20 to about 40° C.) before addingthe anti-solvent. Adding the anti-solvent will effect crystallization orprecipitation of the desired bromfenac sodium Form III in solid form,which may be then separated from the mother liquor by filtration,centrifugation, decantation or other such separation method, washed withsuitable solvent (e.g., an anti-solvent such as tert-butyl methylether), and dried. Suitable alcohols include C₁-C₄ alcohols such asmethanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,tert-butanol and the like and mixtures thereof. Suitable aromatichydrocarbons include aromatic hydrocarbons containing only one aromaticring and optionally substituted with one or more substituents other thanhydrogen, such as C₁-C₄ alkyl groups or halogen. Toluene and xylene areexamples of useful aromatic hydrocarbons. Suitable anti-solventsinclude, but are not limited to, alkylethers such as tert-butyl methylether. The amount of anti-solvent employed preferably is sufficient toeffect precipitation of at least the majority of the bromfenac sodiumpresent in the reaction mixture. In one embodiment of the invention, thesolvents and reagent solutions (e.g., sodium hydroxide solution) arede-aerated prior to use by, for example, bubbling an inert gas such asnitrogen through the solvent or reagent solution.

The present invention further provides processes for converting onepolymorph of bromfenac sodium into a different bromfenac polymorph. FIG.7 illustrates in schematic form certain of the interconversions that arepossible. The particular solvent systems listed in FIG. 7 are forillustrative purposes only and are not meant to be limiting in any way.Also, as used herein, the terms “crystallization” (or “crystallizing”)and “recrystallization” (or “recrystallizing”) are intended to includenot only processes in which a complete solution is achieved at somepoint in the process but also processes in which the material beingcrystallized or recrystallized is never completely solubilized at anypoint. That is, the interconversions may be capable of being achievedusing processes wherein at least a portion of the material beingconverted or processed remains undissolved (i.e., the material/solventmixture takes the form of a slurry of solids in a liquid medium, ratherthan a complete solution).

As previously mentioned, bromfenac sodium Form I may be converted, atleast partially, into bromfenac sodium Form II by drying bromfenacsodium Form I under vacuum. Also, as previously described, bromfenacsodium Form II can be converted into bromfenac sodium Form I byhydrating the bromfenac sodium Form II.

Additionally, a material selected from bromfenac sodium Form I,bromfenac sodium Form II or a mixture of bromfenac sodium Form I andbromfenac sodium Form II may be converted into bromfenac sodium Form IIIby a method comprising crystallizing or recrystallizing the materialfrom a solvent mixture comprised of water and at least one alcohol.Suitable alcohols and crystallization/recrystallization conditions willgenerally be similar to those previously mentioned in connection withthe preparation of bromfenac sodium Form III from bromfenac sodium.

A method for converting bromfenac sodium Form III into bromfenac sodiumForm I is also provided by the present invention. The method comprisescrystallizing or recrystallizing the bromfenac sodium Form III from asolvent mixture comprised of water, at least one dialkoxyalkane, and atleast one anti-solvent such as a dialkyl ether to yield an intermediateproduct containing less than 1.5 moles of water per mole of bromfenacsodium and hydrating the intermediate product. Suitable dialkoxyalkanes,dialkyl ethers, and hydration conditions will generally be similar tothose previously in connection with the preparation of bromfenac sodiumForm I from bromfenac sodium.

The bromfenac sodium polymorphs provided by the present invention areuseful as active ingredients in pharmaceutical formulations employed inthe treatment of various diseases or conditions, particularlyinflammatory conditions. The polymorphs may be utilized as individual,substantially pure polymorphs (i.e., substantially free from otherphysical forms of bromfenac sodium) or as admixtures of two or moredifferent bromfenac sodium polymorphs. Medicinal uses for bromfenacsodium and analogous benzoylphenyl acetic acid salts are well known inthe art and are described, for example, in U.S. Pat. Nos. 4,045,576;4,126,635; 4,182,774; 4,683,242; and 4,910,225 (the disclosure of eachof which is incorporated herein by reference in its entirety for allpurposes). The bromfenac sodium polymorph or polymorphs in accordancewith the present invention may be formulated together with one or moreexcipients such as carriers, solvents, preservatives, stabilizers,surfactants, pH adjusting agents, diluents, fillers, or the like, as maybe desired or needed for purposes of the intended end use. Thepharmaceutical formulation may be in solid or liquid form, such as atablet, capsule, solution, suspension, ointment or the like.

For example, the bromfenac sodium polymorphs of the present inventioncan be used as active ingredients in topically administrable therapeuticcompositions for inflammatory eye disease as well as nasal or oticdisease.

The ophthalmic compositions can be prepared in the form of eye drops,eye ointments and so on in the same manner as various known compositionsfor topical administration to the eye. Thus, a bromfenac sodiumpolymorph or bromfenac sodium polymorph mixture in accordance with thepresent invention can be made up into an aqueous or non-aqueous solutionor mixed with an ointment base suited for ophthalmic use. An aqueousbase such as those generally used in the production of ophthalmicpreparations, for example sterile distilled water, may be suitably usedas the aqueous base. The pH of the ophthalmic preparation is adjusted,if needed, to a level suited for topical administration to the eye. Inone embodiment, an appropriate buffer is added in adjusting the pH. ThepH of the ophthalmic preparation should be selected with dueconsideration paid to the stability and topical eye irritativity of thebromfenac sodium active ingredient, among others. In one embodiment, thestability of an aqueous composition containing the bromfenac sodium isenhanced by incorporating a water-soluble polymer and sulfite, andadjusting the pH to 6.0-9.0, preferably about 7.5-8.5. Illustrativesuitable water-soluble polymers include polyvinyl pyrrolidone,carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,polyvinyl alcohol, sodium salts of polyacrylic acid and the like. Thewater-soluble polymer concentration may be in the range of about 0.1 to10 w/w %, based on the total weight of the solution. Suitable sulfitesinclude sodium sulfite, potassium sulfite, and the like, with thesulfite concentration typically being in the range of about 0.1 to 1.0w/w %, based on the total weight of the solution. The pH adjustment isgenerally conducted with sodium hydroxide or hydrochloric acid, forinstance, and a buffer solution may be formed by combined use of, forexample, sodium acetate, sodium borate or sodium phosphate and aceticacid, boric acid or phosphoric acid, respectively. The ophthalmiccomposition may contain one or more additional pharmaceutically activeingredients, such as an anti-inflammatory agent of another kind, ananalgesic and/or an antimicrobial.

In preparing such ophthalmic compositions, one or more of an isotonizingagent, a microbicidal agent or preservative, a chelating agent, athickening agent and so forth may be added to the compositions inaccordance with the general practice of ophthalmic preparationmanufacture. Suitable isotonizing agents include, among others,sorbitol, glycerine, polyethylene glycol, propylene glycol, glucose andsodium chloride. Illustrative preservatives include para-oxybenzoic acidesters, benzyl alcohol, parachloro-meta-xylenol, chlorocresol, phenetylalcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol, andthe like. The chelating agent may be, for example, sodium edetate,sodium citrate or a sodium salt of condensed phosphoric acid. Inpreparing an ophthalmic composition in the form of an eye ointments, theointment base can be selected from among petrolatum, polyethyleneglycol, carboxymethylcellulose sodium, and the like.

The ophthalmic composition may be prepared by incorporating thebromfenac sodium polymorph or polymorph mixture in a base or vehicle fortopical application to the eye. To prepare a liquid preparation, theconcentration of the active ingredient may range from about 0.001% toabout 10% by weight and is preferably in the range of about 0.01% toabout 5% by weight. An ointment may be prepared by using the bromfenacsodium polymorph or polymorph mixture in a concentration from about0.001% to about 10% by weight, preferably about 0.01% to about 5% byweight. The ophthalmic composition may, for example, be administered inaccordance with any of the following schedules. In the form ofeye-drops, one to several drops per dose are instilled with a frequencyof once to 4 times a day according to the clinical condition. The dosagemay be adjusted according to symptoms.

EXAMPLES Example 1 Preparation of Form III Polymorph of the Sodium Saltof 2-amino-3-(4-bromobenzoyl)phenylacetic acid (Bromfenac Sodium FormIII)

The solvents (toluene and ethanol) used for the reaction were de-aeratedby bubbling nitrogen gas prior to use. A solution of7-(4-bromobenzoyl)indol-2-one (221 g, 0.7 mol; prepared in accordancewith Walsh, D. A.; Moran, H. W.; Shamblee, D. A.; Uwaydah, I. M.;Welstead, Jr., W. J., Sancilio, L. F.; Dannenburg, W. N. J. Med. Chem.1984, 27, 1379-1388) in de-aerated ethanol (0.4 Kg) and de-aeratedtoluene (1.4 Kg) was prepared and further de-aerated by bubblingnitrogen gas. A solution of sodium hydroxide (64 g, 1.61 mol) in water(65 g) was prepared, de-aerated by bubbling nitrogen gas and added, inone portion, to the stirred 7-(4-bromobenzoyl)indol-2-one solution. Theresulting mixture was further de-aerated and while maintaining nitrogengas atmosphere it was heated at 68° C. to 72° C. for 15 h.

The mixture was then cooled to 28° C., tert-butyl methyl ether (1.7 Kg)added and after stirring for 2 h, the solid product was filtered. Thefiltered product was washed with tert-butyl methyl ether (3×0.4 Kg) anddried on the filter at ambient temperature under the vacuum filtrationconditions for 3 h to give the Form III polymorph, as indicated by XRPDanalysis, of the sodium salt of 2-amino-3-(4-bromobenzoyl)phenylaceticacid (284 g) as a yellow solid.

Example 2 Preparation of Form I Polymorph of the Sodium Salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid (Conversion of Form IIIPolymorph into Form I Polymorph)

A 284 g portion of sodium salt of 2-amino-3-(4-bromobenzoyl)phenylaceticacid, Form III polymorph (prepared in accordance with Example 1) wascharged into a reactor and a mixture of water (208 g) and1,2-dimethoxyethane (1.0 Kg) added. The stirred suspension wasde-aerated by bubbling nitrogen gas, then heated at 65° C. to 71° C. for30 minutes. The resulting mixture was allowed to settle for 10 minutesand after removal of the lower aqueous layer, the organic layer wascooled to 67° C. and filtered. The solution was concentrated in vacuo at36° C. to a damp slurry. To the wet slurry was added tert-butyl methylether (1.0 Kg) and the mixture stirred for 1 h. The resultingcrystalline product was filtered, washed with tert-butyl methyl ether(3×0.4 Kg) and dried on the filter under vacuum filtration conditionsfor 3 h to give the Form I polymorph, as indicated by XRPD analysis, ofthe sodium salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid,sesquihydrate (243 g) as a yellow solid.

Example 3 Recrystallization of Form I Polymorph of the Sodium Salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid

A 242 g portion of the sodium salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid sesquihydrate, Form Ipolymorph was charged into a reactor and a mixture of water (262 g) and1,2-dimethoxyethane (2.1 Kg) added. The stirred suspension wasde-aerated by bubbling nitrogen gas, then heated at 65° C. to 70° C. for10 minutes or until a solution was obtained. The resulting solution wascooled to 68° C. and filtered into a jacketed vessel maintained at 60±5°C. A solution of 1,2-dimethoxyethane (0.4 Kg) in tert-butyl methyl ether(1.3 Kg) was prepared and charged while maintaining the temperature at60±5° C. The stirred mixture was then cooled to 10° C. overapproximately 6 hours and maintained at 6° C. to 10° C. for 1 h. Theresulting crystalline product was filtered, washed with tert-butylmethyl ether (2×0.8 Kg) and dried on the filter under vacuum filtrationconditions for 1 h at ambient temperature to give Form I polymorph, asindicated by XRPD analysis, of the sodium salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid, sesquihydrate (148 g) as ayellow solid with 99.95% chemical purity by HPLC.

Sodium Salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid,Sesquihydrate, Form I Polymorph Analytical Data

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.26 (2H, s), 6.46 (1H, dd, J=7.9 Hzand 7.3 Hz), 7.08 (1H, dd, J=8.1 Hz and 1.3 Hz), 7.15 (1H, d, J=7.1 Hz),7.49 (2H, d, J=8.7 Hz), 7.71 (2H, d, J=8.7 Hz), 7.96 (2H, bs, exchangeswith D₂O). ¹³C-NMR (300 MHz, DMSO-d₆) δ (ppm) 197.0, 174.2, 151.7,139.4, 135.2, 131.4, 131.1, 130.6, 126.5, 124.4, 116.7, 114.0 and 44.9.HRMS (ES) calculated for carboxylate ion C₁₅H₁₁BrNO₃ ⁻ 331.9922 [M]⁺ and333.9902 [M]⁺. found 331.9907 [M]⁺ and 333.9893 [M]⁺. FT-IR (KBr) 3538,3416, 3323, 3250-2900 (br), 1618, 1567, 1437, 1416, 1391, 1319, 1244,1172, 1067, 1013, 971, 920, 840, 802 and 752 cm⁻¹. Analysis, calculatedfor C₁₅H₁₁BrNO₃Na.1.5H₂O: C, 47.02; H, 3.68; N, 3.66; Br, 20.85. Found:C, 47.13; H, 3.62; N, 3.80; Br, 20.35. Water content by Karl Fischertitration, calculated for sesquihydrate: 7.05%. Found, 7.2%. XRPDcharacteristic peaks expressed as degrees 2-theta at approximately 4.4,8.8, 9.4, 12.1, 15.2, 15.9, 17.6, 18.2, 18.8, 20.2, 21.2, 24.7, 28.4 and32.4.

Example 4 Preparation of a Mixture of Form I and Form II Polymorphs ofthe Sodium Salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid(Conversion of Form I Polymorph into a Mixture of Form I and Form IIPolymorphs)

The sodium salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acidsesquihydrate, Form I polymorph (148 g) was dried under vacuum (29 inHg) at 33° C. for 6 h and then under vacuum (1.2 mm Hg to 1.6 mm Hg) at30° C. to 32° C. for 12 h to give a mixture of Form I and Form IIpolymorphs, as indicated by XRPD analysis, of the sodium salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid (143 g) as a yellow solid.

FIG. 5 shows the XRPD pattern of a representative sample of a mixture ofthe Form I and Form II polymorphs of bromfenac sodium. A characteristicd-spacing/% intensity pattern for such a mixture is listed in Table C(only the peaks having a relative intensity >2.0% are listed). FIG. 6shows the deduced XRPD pattern for bromfenac sodium Form II (i.e., themain peaks attributable to the Form II polymorph). Table D lists thecharacteristic d-spacing/% intensity pattern attributable to bromfenacsodium Form II in such a mixture.

TABLE C Angle d value, 2-theta Angstrom Intensity % 15.2 5.80 100.0 12.37.18 9.5 23.4 3.79 8.9 17.2 5.13 7.6 20.9 4.24 6.7 26.6 3.34 6.4 18.44.81 6.4 30.2 2.95 6.1 8.6 10.27 5.7 30.7 2.90 5.2 20.6 4.30 5.2 34.02.63 5.1 18.7 4.72 4.9 16.4 5.37 4.2 14.3 6.15 3.3 26.0 3.42 3.2 4.220.54 3.1 12.9 6.84 2.8 22.2 3.99 2.6 10.1 8.74 2.6 7.4 11.81 2.6 11.27.84 2.4 19.3 4.59 2.3 10.4 8.49 2.2 21.7 4.07 2.1 28.9 3.07 2.1

TABLE D Angle d value, 2-theta Angstrom Intensity % 20.7 4.29 100.0 18.54.80 92.2 34.1 2.63 86.4 16.5 5.37 82.2 21.0 4.23 71.2 19.4 4.58 56.117.3 5.12 52.4 14.4 6.14 51.6 22.7 3.91 49.0 29.0 3.07 46.9 11.3 7.8246.7 31.8 2.81 46.5 36.1 2.49 45.9 35.0 2.56 44.4 42.0 2.15 41.4 7.511.74 39.5 46.2 1.96 39.5 38.0 2.37 39.1 8.7 10.20 39.0 13.0 6.83 35.227.7 3.22 34.6 38.4 2.34 32.8 37.6 2.39 32.3

Example 5 Conversion of a Mixture of Form I and Form II Polymorphs intoForm I Polymorph (Hydration in a Glove Bag)

A tray containing a 117.0 g portion of the sodium salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid, Form I and Form IIpolymorph mixture, was placed alongside a tray containing water in aglove bag. The bag was sealed under nitrogen and the product allowed tomoisturize for 5 h at ambient temperature to give substantially pureForm I polymorph, as indicated by XRPD analysis, of the sodium salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid, sesquihydrate (117.3 g) asa yellow solid.

Example 6 Process for the Formation of Form I Polymorph(Drying/Hydration Using a Wet Nitrogen Bleed)

Sodium salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid obtained (5g), obtained after recrystallization from 10% v/v water in1,2-dimethoxyethane-20% v/v 1,2-dimethoxyethane in tert-butyl methylether, was dried under vacuum (29 in Hg) at 30° C. to 33° C. for 5 hwith a slow wet nitrogen gas bleed to give Form I polymorph, asindicated by XRPD analysis, of the sodium salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid, sesquihydrate (4.4 g) as ayellow solid. These conditions were found to be effective in removingresidual organic solvent from the bromfenac sodium while ensuring thatthe sesquihydrate is obtained (i.e., the water content is not reducedbelow 1.5 moles water per mole of bromfenac sodium).

Example 7 Formation of a Mixture of Form I and Form II Polymorphs(Hydration Using a Wet Nitrogen Bleed)

Sodium salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid obtained(26.6 g), obtained after recrystallization from 10% v/v water in1,2-dimethoxyethane-20% v/v 1,2-dimethoxyethane in tert-butyl methylether, was dried under vacuum at 30° C. to 35° C. for 4 h and then underhigher vacuum (30-50 mm Hg) at 31° C. to 33° C. for 10 h with a slow wetnitrogen gas bleed to give a mixture of Form I and Form II polymorphs,as indicated by XRPD analysis, of the sodium salt of2-amino-3-(4-bromobenzoyl)phenylacetic acid, sesquihydrate (26.2 g) as ayellow solid. In contrast to Example 6, these drying conditions wereeffective to remove sufficient water so as to form bromfenac sodium FormII, which is believed to be a monohydrate of bromfenac sodium.

Example 8 Stability of Form I Polymorph

Sodium salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid, Form Ipolymorph (0.6 g) was placed in a drying dish alongside a dishcontaining water (20 g) in a plastic bag. The bag was sealed undernitrogen and the product allowed to moisturize for 19 h. XRPD and watercontent analyses of the product (0.6 g) indicated there was no change inpolymorphic form.

Example 9 Conversion of Form I and Form II Polymorphs into Form IIIPolymorph

To sodium salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid, FormI/Form II polymorph mixture (10 g) was added 5% v/v aqueous 2-propanol(100 mL) and the stirred mixture heated to and maintained at 60-70° C.under nitrogen for 1 h. The mixture was cooled to room temperature andstirred for 1 h. The resulting thick slurry was filtered, washed with2-propanol (2×10 mL) and dried under vacuum (1.5 mm Hg) at 30° C. to 40°C. for 16 h to give Form III polymorph, as indicated by XRPD analysis,of the sodium salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid,non-hydrate (9 g) as a yellow solid.

Sodium Salt of 2-amino-3-(4-bromobenzoyl)phenylacetic acid, Non-Hydrate,Form III Polymorph Analytical Data

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.29 (2H, s), 6.47 (1H, t, J=7.6 Hz),7.09 (1H, dd, J=8.1 Hz and 1.1 Hz), 7.17 (1H, d, J=7.1 Hz), 7.49 (2H, d,J=8.3 Hz), 7.70 (2H, d, J=8.7 Hz), 7.89 (2H, bs, exchanges with D₂O).¹³C-NMR (300 MHz, DMSO-d₆) δ (ppm) 197.0, 174.2, 151.7, 139.4, 135.2,131.4, 131.1, 130.6, 126.5, 124.4, 116.7, 114.0 and 44.9. LCMS m/z 334.1and 332.1 [M]⁺ for carboxylate ion, 290.1, 288.1 (loss of CO₂). FT-IR(KBr) 3437, 3327, 3048, 2921, 1623, 1547, 1432, 1411, 1322, 1280, 1237,1179, 1060, 1005, 963, 938, 840, 823, 798 and 760 cm⁻¹. Analysis,calculated for C₁₅H₁₁BrNO₃Na: C, 50.59; H, 3.11; N, 3.93; Br, 22.44.Found: C, 50.62; H, 3.06; N, 3.93; Br, 22.19. Water content by KarlFischer titration. Found, 0.56%. XRPD characteristic peaks expressed asdegrees 2-theta at approximately 12.2, 12.4, 14.1, 15.5, 16.3, 17.8,18.3, 19.6, 21.6, 22.4, 24.0, 26.3, 26.7, 26.8, 27.2, 28.1, 28.5, 29.7,30.7, 31.0, 31.7, 34.9, 35.7, 36.2, 38.3, 38.7, 39.4, 43.4, 46.9, 47.8and 49.0.

What is claimed is:
 1. Bromfenac sodium, characterized by a powder x-raydiffraction pattern having main peaks expressed as 2-theta at about16.5, 18.5, 20.7, 34.1, 11.3, 14.4, 17.3, 19.4, 21.0, 22.7, 29.0, 31.8,and 36.1 degrees.
 2. A method for making a pharmaceutical formulationcomprising formulating the bromfenac sodium in accordance with claim 1and at least one excipient to provide the pharmaceutical formulation. 3.A method for reducing inflammation comprising administering thepharmaceutical formulation made by the process of claim 2 to an eye of ahuman patient in need of such treatment, wherein the pharmaceuticalformulation is an ophthalmic composition.
 4. The method of claim 3,wherein the pharmaceutical formulation does not contain more than 0.15%AUC of any process impurity of bromfenac sodium degradation product. 5.The method of claim 3, wherein the pharmaceutical formulation containsless than 100 ppm aluminum, boron, and manganese in total and less than30 ppm of each of these elements.
 6. A vial containing thepharmaceutical formulation made by the process according to claim
 2. 7.Bromfenac sodium in accordance with claim 1, characterized by an XRPDd-spacing/% intensity pattern in accordance with that shown in Table D.8. Bromfenac sodium, characterized by a powder x-ray diffraction patternexhibiting main peaks in accordance with those shown in FIG.
 6. 9. Amethod for making a pharmaceutical formulation comprising formulatingthe bromfenac sodium in accordance with claim 8 and at least oneexcipient to provide the pharmaceutical formulation.
 10. The method ofclaim 9, wherein the pharmaceutical formulation is a liquid.
 11. Themethod of claim 10, wherein the liquid is a solution.
 12. The method ofclaim 10, wherein the at least one excipient comprises a water solublepolymer.
 13. The method of claim 10, wherein the crystalline form ofbromfenac sodium consists essentially of bromfenac sodium Form II. 14.The method of claim 10, wherein the pH of the formulation is about 7.5to 8.5.
 15. The method of claim 9, wherein the pharmaceuticalformulation is a suspension.
 16. The method of claim 11, wherein theformulated crystalline form of bromfenac sodium is dissolved in thesolution in an amount from about 0.01% to about 5% by weight.
 17. Themethod of claim 10, wherein the at least one excipient is selected fromthe group consisting of at least one of carriers, solvents,preservatives, stabilizers, surfactants, pH adjusting agents, diluents,and fillers.
 18. The method of claim 9, wherein the at least oneexcipient comprises a preservative, a chelating agent, a pH-adjustingagent, a water soluble polymer, a sulfite, a buffer system, and water.19. The method of claim 18, wherein the pH-adjusting agent comprisessodium hydroxide, the water soluble polymer comprises polyvinylpyrrolidone, the sulfite comprises sodium sulfite, and the buffer systemcomprises boric acid and sodium borate.
 20. The method of claim 19,wherein the chelating agent comprises sodium edetate.
 21. A method forreducing inflammation comprising administering the pharmaceuticalformulation made by the process of claim 9 to an eye of a human patientin need of such treatment, wherein the pharmaceutical formulation is anophthalmic composition.
 22. The method of claim 21, wherein theophthalmic composition is in the form of an eye drop.
 23. The method ofclaim 21, wherein the inflammation is a result of an operative procedureor surgery.
 24. A method for reducing pain comprising administering thepharmaceutical formulation made by the process of claim 9 to an eye of ahuman patient in need of such treatment, wherein the pharmaceuticalformulation is an ophthalmic composition.
 25. The method of claim 24,wherein the ophthalmic composition is in the form of an eye drop. 26.The method of claim 24, wherein the inflammation pain is a result of asurgery.
 27. The method of claim 16, wherein the surgery is cataract orrefractive surgery.
 28. A vial containing the pharmaceutical formulationmade by the process according to claim 9.